Estradiol Regulation of Extracellular Matrix Molecules in the Dorsal Hippocampus of Female Mice

The potent estrogen, 17β-estradiol (E2), can increase hippocampal memory consolidation by enhancing intracellular cell signaling mechanisms in female mice. However, minimal research has been executed on the role of extracellular signaling processes in the effects of E2 on hippocampal memory. The extracellular matrix contains matrix modifying enzymes, such as matrix metalloproteinase-9 (MMP-9), that are important for synaptic plasticity. It has been determined that an MMP-9 inhibitor blocks hippocampal memory consolidation. To establish if E2 interacts with MMP-9 activity in the hippocampus to enhance memory consolidation, we used ovariectomized female C57BL/6 mice, cannulated in the dorsal hippocampus (DH) and dorsal third ventricle (ICV), in object placement and recognition tasks. The mice were trained on either task and then were immediately infused with vehicle or an MMP-9 inhibitor (DH), and vehicle or E2 (ICV). Memory was tested either 24 hours later (object placement) or 48 hours later (object recognition). By inhibiting MMP-9, the enhancing effects of E2 on memory consolidation were consequently blocked; thus, demonstrating that MMP-9 is required for E2 to promote memory formation. Additionally, we found through Western blot analysis that E2 does not influence MMP-9 expression in the dorsal hippocampus, indicating that E2 likely regulates MMP-9 activity, not expression. Future steps include using fluorometric immunocapture assays to test our hypothesis that E2 increases dorsal hippocampal MMP-9 activity. The results from this experiment contribute to the growing understanding of memory formation and may lead to developments in treatments for memory degrading diseases